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Old 07-09-2013, 09:33 PM
gdpawel gdpawel is offline
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Default Functional Profiling Leads to Identification of Accurate Genomic Findings

Robert A. Nagourney, M.D.
Medical & Laboratory Director
Rational Therapeutics

The 2013 American Society of Clinical Oncology annual meeting, held May 31 – June 1, in Chicago, afforded the opportunity to report three studies.

The first, “An examination of crizotinib activity in human tumor primary culture micro-spheroids isolated from patients with advanced non-small cell lung cancer,” reports our experience using the EVA-PCD platform to examine the drug crizotinib. This small molecule originally developed as an inhibitor of the oncogenic pathway MET, was later found to be highly active in a subset of cancer patients who carried a novel gene rearrangement for anaplastic lymphoma kinase (ALK). It was this observation that lead to the drug (sold under the name Xalkori) being approved for the treatment of advanced ALK positive lung cancer. The subsequent observation that this same drug inhibited yet another gene target known as ROS-1 found in a subset of lung cancer patients, has led to its use in this patient population.

Our exploration of crizotinib activity identified a series of patients who received the drug and responded dramatically. This included both ALK positive and ROS-1 positive patients. One patient however, appeared highly sensitive to the drug in our studies, but was found negative for the ALK gene rearrangement by genomic analysis. We repeated our functional analysis only to the find again, the same high degree of crizotinib sensitivity. I felt confident the patient should receive crizotinib, but at the time the drug was not yet commercially available and he didn’t qualify for the protocols, as he was ALK negative.

I scoured the country looking for a way to get the patient treated with crizotinib. From Sloan Kettering to UCLA, no one could help. And then, in collaboration with my abstract co-author Ignatius Ou from UC Irvine, we decided to repeat the ALK analysis. That proved to be a very good idea. For the patient was indeed positive for ALK gene rearrangement by second analysis and subsequently responded beautifully to a treatment for which he would not otherwise qualify. Once again, phenotype trumped genotype.

A final patient in the series represented a particularly interesting application of functional analysis. The patient, a young woman with an extremely rare pediatric sarcoma, had failed to respond to multiple courses of intensive chemotherapy and her family was desperate. As she approached the end of her third year in high school, it looked unlikely that she would reach her senior year. A portion of her tumor was submitted for analysis. The results confirmed relative resistance to chemotherapeutics, many of which she had already received and failed, but showed exquisite sensitivity to crizotinib. Indeed, our inclusion of crizotinib in the analysis reflected our intense effort to identify any activity for this previously refractory patient.

We reported our findings to the pediatric oncologist and encouraged them to consider an ALK rearrangement analysis, despite this particular pathway not being on anyone’s radar prior to our study. The result – a positive gene rearrangement. This led to a successful petition to the drug company for the use of this agent for an off-label indication. The response was prompt and dramatic, and remains durable to this day, nearly a year later. Again, the phenotypic analysis guided us to the correct genomic finding.

Note: Another of the functional cytometric profiling labs has reported out positive for Xalkori (crizotinib) killing tumor cells and killing endothelial cells, with absolutely brilliant responses, in some ALK translocation negative lung cancer patients.
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Last edited by gdpawel : 07-30-2013 at 01:03 AM. Reason: additional info
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Old 07-15-2013, 01:47 AM
gdpawel gdpawel is offline
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Default Physiology Trumps Informatics

According to laboratory oncologists, much like genomics aims to unravel the structure of the genome, metabolomics focuses on understanding the many small molecule metabolites that result from a cell's metabolic processes.

There are an estimated 5,000 - 20,000 endogenous human metabolites, and analysing their production gives an accurate picture of the physiology of a cell at a given moment in time.

Whereas the cell’s genotype can predict its physiology to a limited extent, metabolomics also takes phenotype – and therefore environmental conditions – into account, allowing a more precise measure of actual cell physiology.

For research, the study of metabolomics provides the means to measure the effects of a variety of stimuli on individual cells, tissues, and bodily fluids.

By studying how their metabolic profiles change with the introduction of chemicals or the expression of known genes, for example, researchers can more effectively study the immediate impact of disease, nutrition, pharmaceutical treatment, and genetic modifications while using a systems biology approach.

Just as a cancer genome refers to the complete set of genes, the metabolome refers to the complete set of metabolites in a given tumor. You may need to have the metabolome as well as the genome.

There are many reasons why cancer cures remain out of reach, but several changes could be implemented immediately to increase the rate of success. One of them is the need to redouble the efforts in the study of basic metabolism and the growing field of metabolomics (the metabolome).

Sweeping Study Of Cancer Metabolism Identifies Hundreds Of Alterations And Potential

[url]http://cancerfocus.org/forum/showthread.php?t=3952
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Old 07-16-2013, 11:52 AM
gdpawel gdpawel is offline
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Default Conducting more predictive screens with 3D micro-spheroid cultures

Tissue-mimicking 3D micro-spheroids have been shown to have more physiologically relevant responses to compounds than traditional 2D cultures, bridging the gap between 2D cell cultures and animal and human trials when it comes to screening drugs for cancer.

Three-dimensional (3D) cell culture is already making a big impact on cancer therapy. Rational Therapeutics, based in Long Beach, CA, and the Weisenthal Cancer Group, based in Huntington Beach, CA, are using 3D micro-spheroid culture to provide laboratory-based treatments for cancer patients.

How does it work? First, tumor samples are collected from qualified patients and maintained as micro-spheroids that mimic the body’s environment. The tumor micro-spheroids are then exposed to different drugs and combinations to identify treatments that are most effective at killing the cancer cells. Finally, based on analysis of the results, treatment recommendations are made to help the patients and their physicians determine the best treatment regimens.

According to Rational Therapeutics, the 3D tumor micro-spheroids reflect the complex elements of the body’s cellular environment. The ability to maintain the cells in their native state, where cell-to-cell interactions and heterogeneous cell populations are preserved, has proven critical for the accurate prediction of clinical response.

At the American Association for Cancer Research (AACR) meeting in April 2011, Dr. Robert Nagourney, medical director at Rational Therapeutics and instructor in Pharmacology at the University of California, Irvine School of Medicine, presented findings based on results obtained from primary culture of human tumor micro-spheroids.

Specifically, Dr. Nagourney reported that cancer drugs that target different pathways are more effective when used in combination than alone. By targeting more than one pathway, cancer cells are trapped and killed more easily. The results also demonstrate that biological signals measured from functional cytometric profiling are more powerful and useful than DNA indicators in generating compelling data to aid cancer drug selection.

Sources:
Rational Therapeutics [url]http://www.rational-t.com/
Weisenthal Cancer Group [url]http://weisenthalcancer.com/Home.html
Medicine News Today [url]http://www.medicalnewstoday.com/articles/220677.php
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Old 08-06-2013, 08:37 PM
gdpawel gdpawel is offline
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Default Accuracy and clinical utility of in vitro cytometric profiling to personalize chemo

This study published by ASCO was a collaborative effort with SageMedic of Larkspur, CA, The Ludwig Maximilians University Munich, Germany and the Weisenthal Cancer Group. The study was a meta-analyses that examined the sensitivity and specificity of human tumor primary culture studies and the efficacy of drug therapies selected, based on laboratory findings. In aggregate there were 28 retrospective and 15 prospective trials included.

The overall sensitivity was 0.92 (95 percent C.I. 0.89 – 0.95), and specificity of 0.72 (95 percent C.I. 0.67 – 0.77) with an area under the curve for the ROC of 0.893 (SE = 0.023, p < 0.001). When clinical outcomes were examined, it revealed a two-fold improvement for assay-guided therapy for standard of care (odds ratio 2.04, 95 percent C.I. 1.62 – 2.57, p < 0.001). Finally, the one-year survival rate for assay-guided therapy proved superior (OR 1.44, 95% C.I. 1.06 – 1.95, p= 0.02).

As can be seen from this well conducted meta-analysis, there is a wealth of evidence to support the use of human tumor primary cultures for the selection of chemotherapy.

Accuracy and clinical utility of in vitro cytometric profiling to personalize chemotherapy: Preliminary findings of a systematic review and meta-analysis.

Subcategory: Molecular Diagnostics and Imaging

Session Type and Session Title: This abstract will not be presented at the 2013 ASCO Annual Meeting but has been published in conjunction with the meeting.

Abstract Number: e22188

Citation: J Clin Oncol 31, 2013 (suppl; abstr e22188)

Author(s):

Christian Apfel, Kimberly Souza, Cyrill Hornuss, Larry Weisenthal, Robert Alan Nagourney; SageMedic, Inc, Larkspur, CA; Ludwig Maximilians University of Munich, Munich, Germany; Weisenthal Cancer Group, Huntington Beach, CA; Rational Therapeutics, Long Beach, CA

Background:

Cytometric analysis, or in-vitro functional profiling, has been developed as a method to predict tumor response to different drugs with the premise to personalize chemotherapy and improve patient outcomes.

Methods:

We performed a systematic review and a meta-analysis a) of correlative studies using cytometric profiling that reported diagnostic accuracy (sensitivity and specificity) and b) of effectiveness studies comparing patient outcomes when allocated to treatment guided by a cytometric assay versus population-based standard of care. We used Meta-DiSc software to find pooled sensitivity and specificity and analyze the summary receiver operating characteristic (sROC) curve and used Review Manager 5.1 to generate forest plots on overall tumor response (50% or greater decrease in tumor diameter) and on 1-year overall survival.

Results:

We included 28 mostly retrospective trials (n=664) reporting accuracy data and 15 prospective trials (n=1917) reporting therapeutic efficacy data. The accuracy of correlative study revealed an overall sensitivity of 0.922 (95% confidence interval 0.888 to 0.948), specificity of 0.724 (95% CI 0.669 to 0.774) and an area under the sROC curve of 0.893 (SE=0.023, p<0.001). Studies comparing the clinical utility revealed a two-fold overall tumor response for an assay-guided therapy versus standard of care therapy (odds ratio 2.04, 95% CI 1.62 to 2.57, p<0.001). Similarly, patients who received assay-guided therapy compared to those who received standard of care or physician’s choice had a significantly higher 1-year survival rate (OR 1.44, 95% CI 1.06 to 1.95, p=0.02).

Conclusions:

Despite various limitations of individual studies, the aggregate and fairly consistent evidence of these data suggests cytometric profiling to be accurate, to improve overall tumor response, and to increase 1-year patient survival. Given the enormous potential for our society, a well-designed and sufficiently-powered randomized controlled trial is urgently needed to validate these results.

[url]http://meetinglibrary.asco.org/content/118466-132
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Old 09-16-2013, 09:30 PM
gdpawel gdpawel is offline
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Default Clinical application of human tumor primary culture analyses

The study reviewed the results of 67 patients from institutions across Brazil. Tumor samples were transported by overnight courier to California for drug response profiling. A broad array of tumors were included. The overall success rate provided actionable results in 62 of 67 patients (92 percent). More than 75 percent of the studies provided results for between 8 and 16 drugs and combinations with a median of 12 reported. Several strikingly good responses were observed, including novel combinations identified in the laboratory. This study confirms the feasibility of international collaboration and reflects the globalization of medical care delivery.

International collaboration in personalized medicine for the treatment of advanced and drug-refractory cancers: Clinical application of human tumor primary culture analyses.

Subcategory: Cytotoxic and Other Novel Agents

Session Type and Session Title: This abstract will not be presented at the 2013 ASCO Annual Meeting but has been published in conjunction with the meeting.

Abstract Number: e13562

Citation: J Clin Oncol 31, 2013 (suppl; abstr e13562)

Author(s):

Fabricio Colacino Silva, Fernando C. Maluf, Antonio C. Buzaid, Robert Alan Nagourney, Nise Hitomi Yamaguchi, Paulo D'Amora, Steven Evans, Paula J Bernard, Federico Francisco; Hospital do Cancer Alfredo Abrao, Campo Grande, Brazil; Hospital Sirio-Libanes, São Paulo, Brazil; Hospital São José, São Paulo, Brazil; Rational Therapeutics, Long Beach, CA; Institute of Advances in Medicine and Hospital Albert Einstein, Sao Paulo, Brazil; Centro de Genomas, Sao Paulo, Brazil

Background:

Personalized oncology has advanced through genomic and proteomic platforms. BCR-abl; EGFr and ALK have provided drug-able targets and companion diagnostics in several diseases, yet many transforming events in humans are polygenic, complex and incompletely understood at a genomic level. Recognition that oncogenesis reflects changes in the cell and its micro environment has renewed interest in whole cell experimental models that capture native-state cell-cell, -stroma and -vascular signaling. Ex vivo analysis of programmed cell death (EVA/PCD) has been shown to correlate significantly with response, time to progression and survival (Nagourney, R. Curr. Treat Op Oncol, 2006).To explore EVA/PCD functional profiling in Brazil, hospital-based investigators, Centro de Genomas and Rational Therapeutics coordinated the transport of 67 surgical specimens for analyses.

Methods:

Dose-response curves using metabolic (ATP-content, mitochondrial) and morphologic endpoints, interpolated to LC50's and synergy by median-effect, were compared with databases to identify patient-specific profiles for cytotoxics, targeted agents and combinations. Reports provided day 7.

Results:

62/67 (92%) provided adequate tumor for analysis; 39 male (58%); 28 (42%) female; 6 chemo-naive and 61 previously treated. Results provided for < 8 drugs in 14/62 (22%); 8-16 drugs in 34/62 (54%) and > 16 drugs in 14/62 (22%). Of 22 tumor types, breast (8); Melanoma (8); NSCLC (8); ovary (7); pancreas (7) and sarcoma (4) predominated. EVA/PCD was used to select the most active combinations. Agents selected, response rates and durations are being tabulated and will be reported.

Conclusions:

The transport, processing and reporting of human tumor primary culture analyses is feasible, providing results in 92% of specimens and median of 12 drugs evaluated (range 4-32). Preliminary outcomes in these drug-refractory patients reveal that novel, often unexpected drug combinations (Everolimus and Lapatinib in triple negative breast) were identified and provided objective tumor responses, supporting EVA/PCD in therapy selection (personalized therapy) and drug development.

[url]http://meetinglibrary.asco.org/content/117655-132
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  #6  
Old 09-25-2013, 02:16 AM
gdpawel gdpawel is offline
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Default Gene Testing - Fact versus Fiction

Clinical Trial Finds Personalized Cancer Cytometrics More Accurate than Molecular Gene Testing

In the first head-to-head clinical trial comparing gene expression patterns with Personalized Cancer Cytometric testing (also known as “functional tumor cell profiling” or “chemosensitivity testing”), Personalized Cancer Cytometrics was found to be substantially more accurate.

In the only head-to-head study of gene testing (molecular profiling) versus cytometric profiling to date, cytometric profiling was found to be highly relevant - 90% concordance with treatment outcome - while gene testing was found to be considerably less relevant (0%, 25%, or 75%, depending upon which genes were studied). This rigorous, independently-conducted study was published in a peer-reviewed medical journal.

In a clinical trial involving ovarian cancer patients, patterns of gene expression identified through molecular gene testing were compared with results of Personalized Cancer Cytometric testing (in which whole, living cancer cells are exposed to candidate chemotherapy drugs). Four different genes were included in the molecular part of the study. The four genes were selected as those which researchers believe to have the greatest likelihood of accurately predicting individual patient response to specific anti-cancer drugs.

Study Results: For two of the genes studied, there was no significant correlation between gene expression pattern and patient response. In other words, results for these genes were found to be meaningless. For the third gene studied, there was a 75% correlation between expression and patient response. This means that the gene was 75% accurate when it came to identifying an active drug for that patient. For the fourth gene studied, the accuracy in identifying an active drug was only 25%. In marked contrast, Personalized Cancer Cytometric testing was found by the researchers to be 90% accurate in identifying active drugs for ovarian cancer patients in this study.

Discussion: Molecular testing – that is, testing for gene expression patterns – is widely studied and heavily promoted as a method to identify effective chemotherapy drugs for individual cancer patients. However, most studies of molecular testing carried-out to date show only modest correlation or no correlation between test results and actual patient response. In other words, much work remains to be done before molecular gene testing can be regarded as an accurate tool for chemotherapy selection. And yet in this, first ever, head-to-head study of test accuracy, Personalized Cancer Cytometrics was found to be highly accurate when it came to identifying effective drugs.

Comparing this study with previous studies: Although this was the first head-to-head trial, the accuracy levels found in this trial for Personalized Cancer Cytometric testing are strikingly consistent with those documented in dozens of previous studies, published by respected cancer researchers around the world. In those studies, as in this one, extremely high levels of correlation (in other words, high levels of test accuracy) were found for Personalized Cancer Cytometrics.

Journal Reference and Link to the Actual Study: Arienti et al. Peritoneal carcinomatosis from ovarian cancer: chemosensitivity test and tissue markers as predictors of response to chemotherapy. Journal of Translational Medicine 2011, 9:94.

[url]http://www.translational-medicine.com/content/9/1/94
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Old 03-27-2014, 10:25 PM
gdpawel gdpawel is offline
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Default Is It Ethical to Deny Cancer Patients Functional Analyses?

Robert A. Nagourney, M.D.

The ethical standards that govern human experimentation have become an important topic of discussion. Clinical trials are conducted to resolve medical questions while protecting the rights and well-being of the participants. Human subject committees known as Institutional Review Boards (IRB’s) not only confront questions of protocol design and patient protection but also the appropriateness of the questions to be answered. The Belmont Report (1979) defined three fundamental principles i) respect for persons, ii) beneficence and iii) justice. These have been incorporated into regulatory guidelines codified in the code of federal regulations like 45 CFR 46.111. One historical experience offers an interesting perspective upon contemporary oncologic practice.

[url]http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html

With advances in cardiac surgery in the1970s and 1980s, in both valvular and coronary artery bypass, an alarming amount of post-operative bleeding was being observed. To address this complication an enzyme inhibitor named Aprotinin was developed by Bayer pharmaceuticals. The drug works by preventing the body from breaking down blood clots (thrombolysis). This is critical for the prevention of postoperative bleeding. Concerns regarding its safety led to Aprotinin’s temporary withdrawal from the market, but those have been resolved and the drug is again available.

After Aprotinin’s introduction, clinical trials were conducted to test its efficacy. Initial results were highly favorable as the drug consistently reduced post-op bleeding. By December 1991, 455 patients had been evaluated providing strong statistical evidence that Aprotinin reduced bleeding by more than 70 percent. Despite this, trialists continued to accrue patients to Aprotinin versus “no treatment” studies. By December 1992, more than 2,000 patients had been accrued and by October of 1994, the number had increased to more than 3,800 patients. Yet the 75 percent risk reduction remained entirely unchanged. Thus, 3,400 patients at untold cost and hardship were subjected to the risk of bleeding to address a question that had long since been resolved.

In a 2005 analysis, Dean Fergusson et al, decried that it should have been evident to anyone who cared to review the literature that Aprotinin’s efficacy had been established. Further accrual to clinical trials beyond 1991 only exposed patients to unwarranted risk of bleeding, and had no possible chance of further establishing the clinical utility of the intervention. This stands as a striking lack of consideration for patient well-being. Fergusson’s review raises further questions about the ethics of conducting studies to prove already proven points. With this as a backdrop, it is instructive to examine functional profiling for the prediction of response to chemotherapy.

Beginning in 1997, a cumulative meta-analysis of 34 clinical trials (1,280 patients), which correlated drug response with clinical outcome was reported. Drug sensitive patients had a significantly higher objective response rate of 81 percent over the response rate of 13 percent for those found drug resistant (P < 0.0000001).

[url]http://htaj.com/current.pdf

This was met by the ASCO/Blue Cross-Blue Shield Technology Assessment published in Journal of Clinical Oncology (Schrag, D et al J Clin Oncol, 2004) that cried for further clinical trials. A subsequent meta-analysis correlated the outcome of 1929 patients with leukemia and lymphoma against laboratory results and again showed significantly superior outcomes for assay directed therapy (P <0.001) (Bosanquet AG, Proc. Amer Soc Hematology, 2007).

[url]http://jco.ascopubs.org/content/22/17/3631.full

In response, a second ASCO Guideline paper was published in 2011. (Burstein H et al J Clin Oncol, 2011) Although the authors were forced to concede the importance of the field, they concluded that “participation in clinical trials evaluating these technologies remains a priority.”

[urlhttp://jco.ascopubs.org/content/early/2011/07/18/JCO.2011.36.0354.full.pdf

Most recently we conducted a cumulative meta-analysis of 2581 treated patients that established that patients who receive laboratory “sensitive” drugs are 2.04 fold more likely to respond (p < 0.001) and 1.4 fold more likely to survive one year or more (p <0.02) (Apfel C. Proc Am Soc Clin Oncol 2013).

[url]http://meetinglibrary.asco.org/content/118466-132

Each successive meta-analysis has concluded, beyond a shadow of a doubt, that human tumor functional analyses (e.g. EVA-PCD) identify effective drugs and eliminate ineffective drugs better than any other tool at the disposal of cancer physicians today. Not unlike those investigators who continued to accrue patients to trials testing Aprotinin, long after the result were in, oncologists today continue to clamor for trials to prove something which, to the dispassionate observer, is already patently obvious. If we now pose the question “Is it ethical to deny patients functional analyses to select chemotherapy?” the answer is a resounding No!
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Old 08-23-2014, 02:32 PM
gdpawel gdpawel is offline
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Default You may need to have the metabolome as well as the genome

Cancer is not caused by genetic mutations, mutations are caused by cancer. Cancer is a metabolic disease. The very fact that so many (hundreds of thousands) different types of (unique) mutations are (loosely and unreliably) associated with cancer is just the one clue that cancer medicine has been barking up the wrong (and most expensive) tree.

Cancer is a mitochondrial disease, not a nuclear (DNA-based) disease. Mitochondria are the cell's power generators, and when they become damaged (by radiation, poor diet, viruses, chemicals, etc.), the cell has to resort to primitive process of energy production (fermentation) which is wasteful and messy and damages DNA.

Cancer can best be treated by using a metabolic approach that reduces mitochondrial stress. These metabolic changes are complex and hard to predict. You may need to have the metabolome as well as the genome. Just as a cancer genome refers to the complete set of genes, the metabolome refers to the complete set of metabolites in a given tumor. The altered metabolism of tumors has been considered a target for anticancer therapy.

According to laboratory oncologists, much like genomics aims to unravel the structure of the genome, metabolomics focuses on understanding the many small molecule metabolites that result from a cell's metabolic processes.

There are an estimated 5,000 - 20,000 endogenous human metabolites, and analysing their production gives an accurate picture of the physiology of a cell at a given moment in time.

Whereas the cell’s genotype can predict its physiology to a limited extent, metabolomics also takes phenotype – and therefore environmental conditions – into account, allowing a more precise measure of actual cell physiology.

For research, the study of metabolomics provides the means to measure the effects of a variety of stimuli on individual cells, tissues, and bodily fluids.

By studying how their metabolic profiles change with the introduction of chemicals or the expression of known genes, for example, researchers can more effectively study the immediate impact of disease, nutrition, pharmaceutical treatment, and genetic modifications while using a systems biology approach.

There are many reasons why cancer cures remain out of reach, but several changes could be implemented immediately to increase the rate of success. One of them is the need to redouble the efforts in the study of basic metabolism and the growing field of metabolomics (the metabolome).

Thomas Seyfried: Cancer: A Metabolic Disease With Metabolic Solutions

[url]https://www.youtube.com/watch?v=SEE-oU8_NSU&feature=youtu.be
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Last edited by gdpawel : 05-29-2015 at 03:09 PM. Reason: additional info
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Old 05-07-2015, 09:27 PM
gdpawel gdpawel is offline
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Default Cancer Research Moves Forward by Fits and Starts

Robert A. Nagourney, M.D.

I recently returned from the American Association for Cancer Research (AACR) meeting held in Philadelphia. AACR is attended by basic researchers focused on the molecular basis of oncology. Many of the concepts reported will percolate to the clinical literature over the coming years.

There were many themes including the revolution in immunologic therapy that took center stage, as James Allison, PhD, received the Pezcoller Prize for his groundbreaking work in targeting immune checkpoints. The Princess Takamatsu Award given to Dr. Lewis Cantley, recognized his seminal contribution to our understanding of signal transduction at the level of PI3K. A series of very informative lectures were provided on “liquid biopsies” that examine blood, serum and other bodily fluids to characterize the process of carcinogenesis. These technologies have the potential to revolutionize the diagnosis and monitoring of cancers.

The first symposium I attended described the phenomenon of chromothripsis. This represents a catastrophic cellular trauma that results in the simultaneous fragmentation of chromosomal regions, allowing for rejoining of disparate chromosome components, often leading to malignancy and other diseases. I find the concept intriguing, as it reflects the intersection of oncology with evolutionary developmental biology, reminiscent of the outstanding work of Stephen Jay Gould. His theory of punctuated equilibrium, from 1972, challenged many long held beliefs in the study of evolution.

Since the time of Charles Darwin, we believed that evolution was slow and continual. New attributes were selected under environmental pressure and the population carried those characteristics forward toward higher complexity. Gould and his associate, Niles Eldredge, stated that evolution was anything but gradual. Indeed, according to their hypothesis, evolution occurred as a state of relative stability, followed by brief episodes of disruption. This came to mind as I contemplated the implications of chromothripsis.

According to the new thinking (chromothripsis and its related fields), cancer may arise as a single cell forced to recover from what would otherwise be catastrophic injury. The reconfiguring of genetic elements scrambled together to avoid apoptosis (programmed cell death) provides an entirely new biology that can progress to full-blown malignancy.

By this reasoning, each patient’s cancer is unique. The results of damage control whereby chromosomal material is rejoined haphazardly would be largely unpredictable. These cancers would have a fingerprint all their own, depending on which chromosome was disrupted.

As high throughput technologies and next generation sequences continue to unravel the complexity of human cancer, we seem to be more and more like those who practice stone rubbing to create facsimiles of reality from the “surface” of our genetic information. Like stone rubbing, practitioners do not create the images, but simply borrow from them.

With each symposium, we learn that cancer biology does not come to be, but is. Grasping the complexity of cancer requires the next level of depth. That level of depth is slowly being recognized by investigators from Harvard University to Vanderbilt as the measurement of humor tumor phenotypes.

Cancer is phenotypic and human biology is phenotypic. Laboratory analyses that allow us to measure, grasp, and manipulate phenotypes are those that will provide the best outcomes for patients. Laboratory analyses like the EVA-PCD. [Functional Profiling]
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